The objectives of this program comprise a coordinated approach to the design, synthesis and pharmacological evaluation of chemotherapeutic agents. The guiding principles involve the recognition and exploitation of the structural, electronic and conformational relationships among molecular analogues. Validation of this approach to the design of chemotherapeutic agents should be of both practical and theoretical importance. Particular attention is being directed to the recognition of topological differences of evolutionary origin among enzymes promoting identical reactions in different tissues and organisms, and the exploitation of such differences as the basis for selective toxicity. The principal areas of interest are: 1. The design of compounds suitable for the mass treatment of infections with Schistosoma mansoni and S. japonicum. A number of nitroheterocyclic schistosomicides developed on the basis of these principles are being examined for acute as well as chronic toxicity prior to their clinical trial in man. Studies of the mode of action of these compounds will be continued. Attempts will be made to dissociate mutagenic and carcinogenic properties from antischistosomal activity. On the basis of the elucidation of the role of neurotransmitters in schistosomes, attempts will be made to design compounds which selectively block or enhance the action of neurotransmitters in the parasite. The possible role of hormones in the development of schistosomal reproductive function will be investigated. 2. The development of structural, electronic and conformational analogues of amino acids particularly L-methionine that selectively inhibit the synthesis of S-adenosyl-L-methionine. Some of these agents possess antineoplastic, immunosuppressive and antiinfective properties. Efforts are being made to design analogues with increased therapeutic ratios and to seek other pharmacological applications.